脱碘酶-3 是一种调节足细胞稳态的甲状腺激素。

Deiodinase-3 is a thyrostat to regulate podocyte homeostasis.

机构信息

Department of Internal Medicine, Rush University, Chicago, IL 60612.

Department of Public Health, University of Naples "Federico II," Naples, Italy.

出版信息

EBioMedicine. 2021 Oct;72:103617. doi: 10.1016/j.ebiom.2021.103617. Epub 2021 Oct 11.

DOI:10.1016/j.ebiom.2021.103617

PMID:34649077

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8517284/

Abstract

BACKGROUND

Nephrotic syndrome (NS) is associated with kidney podocyte injury and may occur as part of thyroid autoimmunity such as Graves' disease. Therefore, the present study was designed to ascertain if and how podocytes respond to and regulate the input of biologically active thyroid hormone (TH), 3,5,3'-triiodothyronine (T3); and also to decipher the pathophysiological role of type 3 deiodinase (D3), a membrane-bound selenoenzyme that inactivates TH, in kidney disease.

METHODS

To study D3 function in healthy and injured (PAN, puromycin aminonucleoside and LPS, Lipopolysaccharide-mediated) podocytes, immunofluorescence, qPCR and podocyte-specific D3 knockout mouse were used. Surface plasmon resonance (SPR), co-immunoprecipitation and Proximity Ligation Assay (PLA) were used for the interaction studies.

FINDINGS

Healthy podocytes expressed D3 as the predominant deiodinase isoform. Upon podocyte injury, levels of Dio3 transcript and D3 protein were dramatically reduced both in vitro and in the LPS mouse model of podocyte damage. D3 was no longer directed to the cell membrane, it accumulated in the Golgi and nucleus instead. Further, depleting D3 from the mouse podocytes resulted in foot process effacement and proteinuria. Treatment of mouse podocytes with T3 phenocopied the absence of D3 and elicited activation of αvβ3 integrin signaling, which led to podocyte injury. We also confirmed presence of an active thyroid stimulating hormone receptor (TSH-R) on mouse podocytes, engagement and activation of which resulted in podocyte injury.

INTERPRETATION

The study provided a mechanistic insight into how D3-αvβ3 integrin interaction can minimize T3-dependent integrin activation, illustrating how D3 could act as a renoprotective thyrostat in podocytes. Further, injury caused by binding of TSH-R with TSH-R antibody, as found in patients with Graves' disease, explained a plausible link between thyroid disorder and NS.

FUNDING

This work was supported by American Thyroid Association (ATA-2018-050.R1).

摘要

背景

肾病综合征（NS）与肾脏足细胞损伤有关，可能是甲状腺自身免疫的一部分，如格雷夫斯病。因此，本研究旨在确定足细胞是否以及如何对生物活性甲状腺激素（TH），三碘甲状腺原氨酸（T3）做出反应并进行调节；并解码膜结合硒酶 3 型脱碘酶（D3）在肾脏疾病中的病理生理作用，D3 可使 TH 失活。

方法

为了研究 D3 在健康和受损（PAN、嘌呤霉素氨基核苷和 LPS、脂多糖介导）足细胞中的功能，使用了免疫荧光、qPCR 和足细胞特异性 D3 敲除小鼠。表面等离子体共振（SPR）、共免疫沉淀和邻近连接分析（PLA）用于相互作用研究。

发现

健康的足细胞表达 D3 作为主要的脱碘酶同工型。在足细胞损伤时，体外和 LPS 诱导的足细胞损伤小鼠模型中，Dio3 转录物和 D3 蛋白水平均显著降低。D3 不再定向到细胞膜，而是在高尔基体和核内积累。此外，从小鼠足细胞中耗尽 D3 会导致足突融合和蛋白尿。用 T3 处理小鼠足细胞可模拟 D3 的缺失，并引发αvβ3 整合素信号的激活，从而导致足细胞损伤。我们还证实了小鼠足细胞上存在活性促甲状腺激素受体（TSH-R），其与 TSH-R 抗体的结合可导致足细胞损伤。